This invention relates to processes for preparing controlled release solid dosage forms of lithium carbonate (Li2CO3) for oral administration and controlled release solid dosage forms of lithium carbonate.
Lithium carbonate is indicated in the treatment of manic episodes of manic-depressive illness and is commercially available in controlled release tablets under the tradename Eskalith CR(copyright). In addition to the active ingredientxe2x80x94lithium carbonate, approx. 91%,xe2x80x94Eskalith CR(copyright) tablets contain alginic acid, 1%, gelatin, 4%, sodium starch glycolate, approx. 4%, iron oxide, trace amount, and magnesium stearate, 1%, as inactive ingredients. Eskalith CR(copyright) tablets have been manufactured for a number of years by a high shear wet granulation process that is characterized by a significant time dependent retardation in the dissolution rate of lithium carbonate which results in a shortened shelf-life for the product. Furthermore, significant batch to batch variability in the release rates of the active ingredient, both initially and on storage, is a persistent problem with the current process/product. The batch to batch variability in the release rate of lithium carbonate is of particular concern to the therapeutic use of this agent because lithium toxicity is closely related to serum lithium levels, and can occur at doses close to therapeutic levels. Lithium toxicity is so much of a concern that it is recommended that facilities for prompt and accurate serum lithium determinations be available before initiating therapy with lithium carbonate.
Thus, there is a need in the art for processes for preparing controlled release solid dosage forms of lithium carbonate and controlled release solid dosage forms of lithium carbonate which exhibit batch to batch consistency in release rates and stabilized dissolution profiles over time.
As disclosed herein, suitable controlled release solid dosage forms of lithium carbonate and processes for preparing the same have now been discovered
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth.
By the term xe2x80x9chydrophobic waxy materialxe2x80x9d, xe2x80x9cwaxy materialxe2x80x9d or xe2x80x9cwaxxe2x80x9d as used herein, is meant a fatty acid, alcohol or ester, alone or an admixture thereof. More specifically, the fatty acid may have from about 10 to about 22 carbon atoms and may be, for example, decanoic, stearic, palmitic, lauric or myristic acid.
The fatty alcohols may have from about 14 to about 31 carbon atoms and may be, for example, lauryl alcohol. cetyl, stearyl, myristyl, carbucyl or ceryl alcohol.
The esters may be mono-, di-, or triglyceryl esters. The hydrophobic waxy material may be modified by waxy materials of natural or synthetic sources. Exemplary of such waxes are beeswax, spermaceti wax or carnauba wax.
Preferred hydrophobic waxy materials for use herein include: cetyl alcohol, carnauba wax, glyceryl behenate (Compritol(copyright) from Gattefosse Corp.) glyceryl palmitostearate (Precirol(copyright) from Gattefosse Corp.) glyceryl monostearate and glyceryl distearate.
By the term xe2x80x9cdissolution rate stabilizerxe2x80x9d as used herein is meant organic acids such as fumaric acid, citric acid, tartaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, sorbic acid and their anhydrides and salts. Poorly water soluble acids are preferred. Particularly preferred acids for use herein are fumaric acid and malic acid.
By the term xe2x80x9cformulated into solid dosage formsxe2x80x9d and derivatives thereof, as used herein preferably includes filling hard gelatin capsules and compressing into tablets.
By the term xe2x80x9cthermal infusionxe2x80x9d and derivatives thereof, as used herein is meant that the pharmaceutically active materialxe2x80x94lithium carbonatexe2x80x94is blended with a hydrophobic waxy material and optional pharmaceutically acceptable excipient(s) and then optionally compacted, followed by dry granulation in a granulator at a suitable thermal infusion temperature and then optionally milled and screened to form thermal infusion granules.
When referring to thermally infusing blends in which the percentage of hydrophobic waxy material is about 30% by weight, preferably less than 20%, in relation to the pharmaceutically active material, the term xe2x80x9csuitable thermal infusion temperaturexe2x80x9d or xe2x80x9cthermal infusion temperaturexe2x80x9d and derivatives thereof, as used herein includes ambient temperature and temperatures above the extrapolated onset temperature, preferably less than 15xc2x0 C. above the melting temperature, of the hydrophobic waxy material.
The xe2x80x9cextrapolated onset temperaturexe2x80x9d represents that temperature corresponding to the intersection of the pre-transition baseline with the extrapolated leading edge of the endotherm (melting curve). For glyceryl behenate the extrapolated onset temperature is about 68xc2x0 C.
Additional aspects relating to thermal infusion are found in International Publication Number WO 94/27557, having an International Publication Date of Dec. 8, 1994, the entire specification of which is hereby incorporated by reference.
The present invention relates to a process for preparing controlled release solid dosage forms of lithium carbonate (Li2CO3) which comprises blending lithium carbonate, a hydrophobic waxy material, preferably glyceryl behenate, a dissolution rate stabilizer, preferably fumaric acid, and optional pharmaceutically acceptable excipient(s), preferably microcrystalline cellulose, in a suitable mixer. The blend is converted into granules of desired particle size distribution by a dry granulating process which preferably consist of the steps of roller compacting, milling and screening. The granules thus prepared are formulated into solid dosage forms.
The order in which the indicated ingredients are utilized in the presently invented process is not critical. All orders of addition of the indicated ingredients are within the scope of the invention. However, the most advantageous process comprises blending lithium carbonate, in about 40 to 90% by weight preferably 65 to 85% most preferably 80 to 85%, a hydrophobic waxy material, preferably glyceryl behenate, in about 5 to 30% by weight preferably 5 to 25%, most preferably 8-23% in relation to the pharmaceutically active material, and optional, pharmaceutically acceptable excipient(s), preferably microcrystalline cellulose, in about 5 to 10% by weight, in a suitable mixer. The blend is converted into granules of desired particle size distribution by a dry granulating process which preferably consist of the steps of roller compacting, milling and screening. The granules thus prepared are blended with a dissolution rate stabilizer, preferably fumaric acid, in an amount greater than 1% to about 15% by weight, preferably 3 to 15%, most preferably about 6 to 13%, and a pharmaceutically acceptable excipient, preferably microcrystalline cellulose, in about 5 to 30% by weight, preferably 10 to 25%, most preferably 10 to 20%. in a suitable mixer and formulated into solid dosage forms.
In noting the percentages of the ingredients above and throughout the specification and the claims, the wax content as well as the other excipients are always stated in relation to the active material (for example, 85/15 means 85 parts of lithium carbonate blended with 15 parts of an excipient such as glyceryl behenate or 80/15/5 means 80 parts of lithium carbonate, 15 parts of an excipient such as glyceryl behenate and 5 parts of an excipient such as microcrystalline cellulose).
An alternative step in the presently invented process involves subjection of a blend, prepared as described herein, to thermal infusion prior to or during the dry granulating process.
The ability of the presently invented process to prepare the presently invented controlled release solid dosage forms of lithium carbonate, which exhibit batch to batch consistency in release rates and stabilized dissolution profiles over time, is primarily attributed to the addition of a dissolution rate stabilizer to the formulation and using a dry granulating process instead of a wet granulating process as was previously used.
Additional pharmaceutically acceptable excipients which are contemplated for use in the process and compositions of the present invention include release rate modulating polymers, such as high molecular weight poly(ethylene oxide) (available under the name Polyox WSR of Union Carbide Corporation), lactose, polyvinylpyrrolidone and pharmaceutically acceptable coloring agents.
In a general procedure for the processes of the current invention, lithium carbonate, a hydrophobic waxy material and optional pharmaceutical excipients are blended in a suitable mixer and granules of desired particle size distributions are manufactured in a dry granulating process, preferably by slugging or compacting, milling and screening. The granules may be produced using a continuous process or a batch process. Granules of desired mesh size (such as  less than #18 and  greater than #80 mesh. i.e., passing through #18 mesh sieve but retained on #80 mesh sieve) are prepared, optionally by subjecting a blend, prepared as described herein, to thermal infusion prior to or during the dry granulating process.
The granules thus prepared are blended with optional pharmaceutical excipients and a dissolution rate stabilizer, preferably an organic acid such as fumaric acid, and filled into hard gelatin capsules or compressed into tablets. In another variation of the process, the powdered blend is granulated by melt granulation instead of by roller compaction. This melt granulation is milled to produce granules with a desired particle size distribution. These granules are blended with optional pharmaceutical excipients and a dissolution rate stabilizer, preferably an organic acid, and filled into hard gelatin capsules or compressed into tablets.
By the term xe2x80x9cpharmaceutically acceptable excipientsxe2x80x9d as used herein is meant additives such as diluents, fillers, and binders which are optionally utilized in accordance with the process of the present invention. The excipients commonly used in pharmaceutical industry are well described in literature such as described in Handbook of Pharmaceutical Excipients, A. Wade and P. J. Weller (Editors), American Pharmaceutical Association (1994). Pharmaceutically acceptable fillers and diluents include but are not limited to lactose (hydrous as well as anhydrous), starch [unmodified (corn starch) or modified (for e.g., Starch 1500 available from Colorcon)], mannitol, sorbitol, cellulose, inorganic sulfates and phosphates. Pharmaceutically acceptable binders include but are not limited to gelatin, corn starch, modified starch (Starch 1551, pregelatinized starch). hydroxypropyl methyl cellulose (HPMC) and hydroxypropyl cellulose(HPC). Examples of excipients suitable for modified release applications in accordance with the present invention include but are not limited to) waxy materials such as glyceryl behenate (Compritol(copyright)), glyceryl palmitostearate (Precirol(copyright)), saturated polyglycolyzed glycerides (Gelucire(copyright)) [all from Gattefosse s.a., France], carnauba wax and a series of high molecular weight non-ionic water-soluble high molecular weight poly(ethylene oxide) polymers (Polyoxe(copyright) WSR, Union Carbide Corp.).
The present invention also relates to novel compositions of lithium carbonate prepared by the dry granulating process described above. The presently invented compositions of lithium carbonate comprise lithium carbonate, a hydrophobic waxy material, preferably glyceryl behenate, a dissolution rate stabilizer, preferably fumaric acid, and optional pharmaceutically acceptable excipient(s), preferably microcrystalline cellulose.
The presently invented compositions of lithium carbonate suitably comprise lithium carbonate, in about 40 to 90% by weight preferably 65 to 85% most preferably 80 to 85%, a hydrophobic waxy material, preferably glyceryl behenate, in about 5 to 30% by weight preferably 5 to 25%, most preferably 8-23% in relation to the pharmaceutically active material, pharmaceutically acceptable excipient(s), preferably microcrystalline cellulose (added extragranularly or both intra- and extra-granularly), in about 5 to 30% by weight, preferably 10 to 25%, most preferably 15 to 25%, and a dissolution rate stabilizer, preferably fumaric acid in an amount greater than 1% to about 15% by weight, preferably 3 to 15%, most preferably 6 to 13%.
A further contemplated aspect of the presently invented process and compositions relates to subsequently coating the prepared compositions with a moisture barrier or controlled release polymer coating.